Thromboembolic complications (TEC) have been observed in some clinical trials of anti-CD40L (CD40L is abbreviated for CD40 ligand, also known as CD 154) antibody, in particular, humanized monoclonal antibody directed against CD40L. Known to be expressed by activated T cells, CD40L was also shown to be present on the surface of activated human platelets and may play a role in endothelial cell activation in vitro (Henn et al., Nature, 1998, 391, 591-594). However, the role of the CD40/CD40L pathway in regulating coagulation in vivo at the level of platelet/endothelial cell interaction is still undefined.
CD40L is a type II membrane protein first described to be expressed on activated T cells. The interaction of CD40L with its receptor, CD40, is critical for B cell differentiation, proliferation, and immunoglobulin (Ig) isotype switching induced by helper T cells (Foy et al., Annu. Rev. Immunol., 1996, 14, 591-617; and van Kooten et al., J. Leukoc. Biol., 2000, 67, 2-17). The involvement of the CD40/CD40L pathway in the interaction of platelets with endothelial cells has recently been described (Henn et al., Nature, 1998, 391, 591-594). Under normal conditions, CD40L is stored in platelets. Upon activation, CD40L is translocated to the surface of platelets accompanied by surface appearance of CD63, P-selectin, and several other proteins, as well as release of soluble mediators from intra-platelet granules (Murano G., Basic Concepts of Hemostasis and Thrombosis, 1980, Boca Raton, Fla., CRC Press, Inc.). Hence, CD40L may play a role in procoagulant activity.
Elevated levels of soluble CD40L (sCD40L) have been found in the blood of lupus patients (Kato et al., J. Clin. Invest., 1999, 104, 947-955; and Vakkalanka et al., Arthritis Rheum., 1999, 42, 871-881). Rheumatoid factor (RF), an autoantibody to the Fc portion of Ig, is often detected in the sera of patients with autoimmune disorders (Mageed et al., Ann. N.Y. Acad. Sci., 1997, 815, 296-311). Additionally, the administration of anti-CD40L antibody could result in the production of antibodies directed against anti-CD40L antibody.